Apolipoprotein E (apoE) is a 299 amino acid protein that plays a palliative role in the CNS response to acute and chronic injury. We have recently demonstrated that the addition of exogenous apoE, or peptides derived from its receptor-binding domain, can reduce endogenous CNS inflammatory response. As a 20mer, this peptido-apoE-mimetic appears to act as an agonist on the LRP receptor (Low Density Lipoprotein receptor-related protein) and could have beneficial effects in whole animal models and ultimately, in human patients. Although modifications of this peptide may improve neuroprotective activity, our ultimate goal is to create a non-peptido-mimetic of apoE?s activity. Thus, in PHASE 1 of this proposal, we propose to extensively modify this lead compound, i.e. the 20 amino acid peptido-apoE-mimetic, to more precisely define its minimal and essential residues that retain binding and biological activities. In PHASE 2 of this proposal, we will make use of this SAR data (Structure-Activity Relationship) to learn how to define the space that this peptide occupies in the LRP receptor and then use this information to direct the synthesis of non-peptide molecules that can similarly act as LRP agonists in cell-based and animal-based model systems. PROPOSED COMMERCIAL APPLICATION: Following brain injury that results from stroke and closed head injury, peptides and/or compounds that protect neurons from dying would be of clinical and therapeutic benefit to the patient. Based on the demonstrated involvement of apolipoprotein-E in human brain injury, we are developing novel apoE-mimetics that help protect against neuronal death in human brain injury.